van Wijk P A, Rijnberk A, Croughs R J, Meij B P, Mol J A
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
Eur J Endocrinol. 1998 Mar;138(3):309-15. doi: 10.1530/eje.0.1380309.
Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions. Under basal conditions, no significant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol. The CRH-induced ACTH secretion by corticotrophic adenoma cells was significantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP- or IGF-I-stimulated conditions. The relative inhibition was, however, significantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h. In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growth-promoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours.
诸如下丘脑激素或垂体内部生长因子等外在因素可能刺激基因组改变细胞的克隆扩增，因此在垂体肿瘤发生中发挥作用。在此，我们报告促垂体激素促肾上腺皮质激素释放激素（CRH）和血管加压素（AVP）以及垂体内部生长因子胰岛素样生长因子-I（IGF-I）对正常犬垂体细胞以及垂体依赖性肾上腺皮质功能亢进犬的促肾上腺皮质激素腺瘤细胞增殖（通过溴脱氧尿苷标记指数测量）和促肾上腺皮质激素分泌的影响。在各种条件下分析了对皮质醇抑制的敏感性。在基础条件下，对照细胞和肿瘤细胞之间的溴脱氧尿苷标记指数未发现显著差异。CRH、AVP、IGF-I和皮质醇对犬垂体细胞或犬促肾上腺皮质激素腺瘤细胞的增殖均无影响。与正常垂体细胞相反，促肾上腺皮质激素腺瘤细胞的增殖受到胎牛血清（FCS）的刺激。这种FCS诱导的增殖不受皮质醇抑制。用CRH孵育4小时后，促肾上腺皮质激素腺瘤细胞中CRH诱导的促肾上腺皮质激素分泌明显（P<0.05）低于正常垂体细胞。在基础以及AVP或IGF-I刺激条件下，用皮质醇孵育24小时导致促肾上腺皮质激素分泌减少。然而，产生促肾上腺皮质激素的肿瘤细胞中的相对抑制明显（P<0.05）低于正常垂体细胞。24小时后，皮质醇未抑制正常垂体细胞中CRH诱导的促肾上腺皮质激素分泌。总之，犬促肾上腺皮质激素腺瘤对CRH刺激的敏感性较低，对糖皮质激素抑制的敏感性也较低。这些肿瘤对FCS中存在的一种生长促进因子具有异常敏感性。该因子可能在犬促肾上腺皮质激素肿瘤的生长促进中起重要作用。
